Fibroblast Growth Factor Receptor (FGFR) is a type of receptor tyrosine kinase (RTK) structurally composed of an extra-membrane ligand binding domain, a single transmembrane domain, and an intra-membrane tyrosine kinase. It mainly includes four subtypes, FGFR1, FGFR2, FGFR3 and FGFR4. It and its ligand, Fibroblast Growth Factor (FGF) play an important regulatory role in cell signaling. As an extracellular stimulatory signal, FGF binds to the extracellular domain of FGFR, causing phosphorylation of its intra-membrane tyrosine kinase, thereby activating a series of downstream signaling pathways that regulate cell proliferation, differentiation and metastasis.
A variety of tumors are closely related to FGF/FGFR expression and activation, such as non-small cell lung cancer, breast cancer, gastric cancer, liver cancer, bladder cancer, endometrial cancer, prostate cancer, cervical cancer, colon cancer, esophageal cancer, myeloma and melanoma, and so on (Clin. Cancer Res. 2012, 18, 1855). Studies have shown that FGFR1 amplification accounts for 20% of non-small cell lung cancer, FGFR2 amplification accounts for about 5% of gastric cancer, FGFR3 mutation accounts for about 70% of non-invasive bladder cancer, and FGFR4 is amplified in liver cancer (PloS One 2012, 7, e36713). Therefore, the development of inhibitors targeting FGFR has become a hot topic in anti-tumor drug research (Drug Disc. Today 2014, 19, 51).
There are currently some non-FGFR-specific drugs on the market, such as sunitinib from Pfizer, lenvatinib from Eisai, and nintedanib from Boehringer Ingelheim, but there is no FGFR-specific inhibitor currently available. Specific FGFR inhibitors that enter the clinics include HMPL-453, BGJ-398, LY-2874455, AZ-4547, JNJ-42756493, TAS-120, ARQ-087, and BLU-554.
The development of FGFR inhibitors has attracted the attention of many biopharmaceutical companies, yet new compounds still need to be developed due to their promise in the treatment of various malignant tumors. Through continuous efforts by the inventors, the present invention has designed a compound having a structure represented by the general formula (I), and it has been found that a compound having such a structure exhibits an excellent function and effect.